Picornaviridae are a large group of single-stranded RNA viruses that cause infections such as viral meningitis, encephalitis, viral respiratory infection and viral exacerbation in asthma and colds (Picornaviridae and Their Replication; Second Edition, edited by B. N. Fields et al., New York, 1990). Picornaviruses were among the first viruses recognized and encompass approximately 230 serotypes divided into five genera that include apthovirus, cardiovirus, enterovirus, hepatovirus and rhinovirus. Enterovirus and rhinovirus, which cause the common cold, comprise most of the known picornavirus serotypes.
The replication of single-stranded RNA viruses such as picornaviruses occurs entirely in the cytoplasm and has been well characterized. Briefly, the genome of picornaviruses consists of one single-stranded (+)-sense RNA molecule that encodes a single polyprotein, typically between about 2100 amino acids and about 2400 amino acids in length. The polyprotein is processed through proteolytic cleavage to provide viral proteins such as a picornavirus protease, a virus RNA-dependent RNA polymerase and various coat proteins. The cleavage of the polyprotein into the above proteins is highly specific and may provide an attractive target for pharmaceutical intervention. A significant problem in developing effective pharmaceutical treatment of picornaviral infections, however, is the rapid mutation rate of RNA viruses. This rapid mutation rate might be caused by the absence of any error-correcting mechanisms in RNA synthesis.
The cellular receptors of a number of different picornaviruses have been identified using a number of conventional techniques (for example, binding competition between different viruses, monoclonal antibodies that prevent virus binding and fluorescently labeled virus). Prevention of virus binding to cellular receptors is another attractive area for pharmaceutical intervention (Heinz et al., J. Virol., 1989, vol. 63, pp. 2476). Picornaviruses have also been characterized by X-ray crystallography (Rossman et al., Nature, 1985, 317, 145), which has been of great value in rationally designing inhibitors that interfere with virus-receptor binding.
Picornaviruses, particularly those of enterovirus and rhinovirus genera cause significant numbers of human viral infections each year. Effective therapies for the majority of picornaviral infections are inadequate or simply unavailable. Thus, there is a general need for agents active against picornaviruses and a specific need for agents active against enteroviruses and rhinoviruses.
U.S. Pat. No. 4,843,087 discloses diheterocylic compounds for use as anti-viral agents. U.S. Pat. Nos. 5,349,068 and 5,464,848 disclose 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as anti-picornaviral agents.
Citation or identification of any reference in Section 2. of this Application is not an admission that any such reference is available as prior art to the present invention.